Case Study 1 - Telstar®
Transcript of Case Study 1 - Telstar®
CASE STUDY Implementation of the SmartCR in an aseptic processing facility. Airflow reduction and energy savings achieved in HVAC compared to conventional systems
The challenge of reducing HVAC energy consumption and operation
costs without negatively affecting the quality of the finished products,
ensuring cleanrooms always conform to required specifications
© Azbil Telstar. March 2020
© Azbil Telstar. March 2020
www.telstar.com
A B S T R A C T
The SmartCR is an innovative flexible solution for cleanrooms that adjusts air changes which reduces energy
consumption and operation costs, ensuring cleanrooms always conform to required specifications. The
adjustment is done through the HVAC control system, considering inline particle counters, differential
pressure transmitters and temperature and relative humidity probes.
This study explains the implementation of the technology in a new aseptic processing facility. In order to
evaluate the energy savings reached, the different tests performed are described and the results are
compared to conventional HVAC systems. Commissioning and Qualification strategy is also presented.
It demonstrates how the new system effectively responds to the high quality demanding pharmaceutical
industry standards, ensuring the stability of the critical parameters of the controlled environment at all
times.
Background The SmartCR technology has been implemented in the
frame of a newly constructed aseptic facility for liquid
and lyophilized products, starting from Conceptual
Design, followed by a Basic and Detailed Design.
The core of the process consists of a complete
automated aseptic filling line, provided with an
automated vials washing machine connected to a
depyrogenation tunnel installed in a D grade area.
Sterilized and depyrogenated vials are then transferred
to the aseptic area, where the automatic filling
machine, under laminar flow is installed. Filled and
stoppered vials are transported by a conveyor inside
an ORABS (under laminar flow). They can be
automatically introduced in one of the two freeze-
dryers and/or transported into the capping machine
(also under laminar flow). All high risks operations are
conducted in A-grade conditions in a B-grade
background environment and manual operations have
been minimized.
Current European GMP Annex 1 as well as its new draft
was taken into consideration from the early stages,
including requirements on environmental monitoring.
System description
HVAC in aseptic area
The new aseptic filling and lyophilisation facility is
served by 5 air handling units (AHU) and 1 make-up
air unit. The SmartCR was implemented on the AHU
serving the 9 cleanrooms in the aseptic area (140 m2),
taking advantage of the inline continuous airborne particle
counting system already foreseen.
Inside the aseptic area, 6 laminar flow units and 1 ORABS
provide 35 m2 of A-grade area, with a B-grade environment
of 105 m2. The SmartCR acts and regulates supply air of
the B-grade environment (turbulent flow).
According to regulations, the HVAC system guarantees a
differential pressure of 15 Pa between B-grade and
surrounding C-grade. In addition, a differential pressure of
15-10 Pa between some rooms of the same grade has
been considered to create an air pattern.
The AHU works in recirculation mode (with a fresh air
portion for ventilation purposes). To supply and return the
appropriate airflows and regulate and control differential
pressures, the HVAC system is provided with motorized
supply and return dampers, as well as differential pressure
transmitters and EC fans (with proportional regulation).
Airborne Particle Counting System
The number and placement of the particle counters was
studied and defined based on a risk-analysis. Operations
performed in each room, personnel, material and waste
flows were studied, risks identified and their severity,
probability and detectability assessed.
The continuous airborne particle counting system is
CASE STUDY
.© Azbil Telstar. March 2020
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composed of a centralized vacuum system for sample
acquisition controlled by a PLC and the 2-channel
counters (0.5 µm and 5.0 µm). The number of
particles in air samples is registered and saved in a
database every 30 seconds.
The continuous measure of particles ensures the
reliability of the system.
Building Management System
The new aseptic filling and lyophilisation facility is
provided with a centralized BMS control system with
all data recorded and stored in a unique database, all
parameter settings are audited and all configurations
are GAMP V, and 21CFR Part 11 compliant. Both the
HVAC and APC PLC controllers are connected to a
SCADA application with a historian database and audit
license.
SmartCR Functionality
Similar to conventional cleanroom HVAC systems,
room temperature and relative humidity are regulated
by means of probes installed in return ducts and
regulation valves for chilled and heating water
installed on the AHU coils; and room differential
pressure is regulated by means of transmitters and
motorized dampers in return ducts.
However, in ECO mode, the supply air is not a fixed
airflow to provide a certain number of air changes per
hour (ACH) as recommended in guidelines and good
design practices or based on experience (typically,
ISPE recommendations for EU Grade B are 40-60
ACH), hereinafter referred to as Design Flow. The
supply airflow varies to meet cleanroom parameters
within limits: maximum admissible number of
particles, differential pressures, temperature and
relative humidity. For this purpose, the airborne
particle counter captures are considered in airflow
regulation.
As a consequence, the airflow varies from the Design
Flow to the Minimum Flow.1
1 The Minimum Flow is established during start-up and Commissioning
of the system
Figure 1. Airflow evolution during reduction phase and increase up to Design Flow
In ECO mode, the system can only start reducing the
airflow if the following conditions are met:
▪ HVAC & APC PLCs connected and communicating
▪ Supply & return fans working properly
▪ No alarms in cleanroom differential pressures
▪ No alarms in temperature and relative humidity
▪ No alarms in airborne particle counters and
number of particles below previously established
limits
Once the cleanroom parameters are within limits, the
SmartCR starts gradually decreasing the AHU supply fan
speed in controlled steps until reaching the established
Minimum Flow.
In these conditions, if a perturbation drives the cleanroom
out of specifications SmartCR starts gradually increasing
the AHU fan speed up to the Design Flow to return fast
within the specified limits of temperature, relative
humidity, differential pressure and maximum admissible
number of particles. Once the cleanroom returns within the
limits, the system starts reducing the AHU fan speed
gradually again after an established period of time.
Design Flow
Minimum Flow
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Parti
cle
s (
CFM
)
Air
flow
(m
³/
h)
AIRFLOW vs PARTICLE < 0,5 µm
Q (m³/h) Part < 0,5 µm (CFM)
SCR Limit (CFM) GMP Limit (CFM)
Figure 2: Airflow evolution from Design Flow to Minimum Flow and a perturbation generated by particles <0,5µm and driving the SmartCR to an increase of airflow
Design Flow
CASE STUDY
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words, up to 32 trolleys can be placed in two rows in each autoclave. The bags arrive from the filling line through a conveyor system and are manually positioned on the trays. Subsequently, another operator houses the trays in each of the trolleys. These have guides to accommodate up to 10 levels of trays.
SmartCR Configuration
There are several parameters that can be configured
to adapt the SmartCR to the final user needs and the
particularities of each installation. This configuration
takes place during the start-up and commissioning of
the system.
- Minimum Flow: it is the minimum airflow to
guarantee the cleanroom parameters are
always inside the limits (temperature, relative
humidity, max. admissible number of particles
and differential pressure). The user can limit the
Minimum Flow. It can be limited to comply with
internal polices (for example, a minimum air change
rate) or HSE requirements (ventilation). By default,
it is the lowest to ensure the maintenance of the
environmental conditions within the specified limits
in order to obtain the maximum energy saving, but
always preserving an acceptable recovery time in all
cleanrooms served by the AHU.
- Max. Admissible Number of Particles: The user
can limit the values established in regulations. The
Maximum Admissible Number of Particles can be
limited setting the ECO offsets. Default values are
those set in EU GMP.
- Flow Step & Stabilization Time: The user can
select the step of airflow reduction. Between two
steps of airflow reduction, there is a stabilization
time. Dampers and airborne particle counters
captures react and
adjust the system. Big
steps can affect
differential pressure
stability, while very
small steps can make
the airflow reduction
phase too slow.
- Ramp Time: When there is a perturbation driving
the cleanroom out of specifications, the airflow
increases up to the Design Airflow in a pre-set time
called Ramp Time. An appropriate time to reach
Design Flow after a perturbation ensures the
stability of the system and the recovery times.
A balance must be found in start-up and commissioning.
Commissioning & Qualification
Commissioning
The start-up and commissioning of the system is
performed as for conventional systems but executing some
additional specific tests for SmartCR implementation. As
previously explained, a balance between flow step
adjustment and stabilization time is searched to define the
Minimum Airflow.
Then, the environmental conditions are observed during at
least 12 hours to verify they rest within the specified limits
and the stability of the system.
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flow
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³/
h)
AIRFLOW vs PARTICLE < 5 µm
Q (m³/h) Part < 5 µm (CFM)
SCR Limit (CFM) GMP Limit (CFM)Figure 3: Evolution of < 5 µm-Particles measures during test shown in Figure 2
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cle
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flow
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³/
h)
AIRFLOW vs PARTICLE < 5 µm
Q (m³/h) Part < 5 µm (CFM)
SCR Limit (CFM) GMP Limit (CFM)
Figure 4: Airflow evolution from Design Flow to Minimum Flow and a perturbation generating particles <5µm and driving the SmartCR to an increase of airflow
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cle
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CFM
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flow
(m
³/
h)
AIRFLOW vs PARTICLE < 0,5 µm
Q (m³/h) Part < 0,5 µm (CFM)
SCR Limit (CFM) GMP Limit (CFM)
Figure 5: Evolution of <0,5 µm-particles measures during test shown in Figure 4
Figure 6: Airflow reduction steps
CASE STUDY
.© Azbil Telstar. March 2020
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After that, the system is challenged by producing
temperature and relative humidity excursions. The
capacity of the system to recover room conditions is
tested.
Finally, there is a phase of verification of the
differential pressures stability at the Minimum Airflow,
simulating production operations, opening doors, etc.
Qualification
Since the supply airflow varies inside a range, a risk
analysis was performed to assess if the qualification
tests should be conducted at Design Flow or at
Minimum Flow. Critical Quality Attributes (CQA) and
the related critical material attributes (CMA) and
Critical Process Parameters (CPP) were studied.
GRADE B
Critical Quality Attributes Critical Process Parameters / Critical Material Attributes
Particle concentration (in operation) HEPA filters’ integrity
Rooms’ differential pressure
Particle concentration (at rest)
Recovery time Air change rate
Microbiology concentration HEPA filters’ integrity
Differential pressure
▪ HEPA Filters’ Integrity: Not affected by the flow.
▪ Differential Pressure: Since the variability of the
supply airflow and the return dampers reaction
directly affects differential pressures, this
parameter should be verified in all the airflow
range (Design Airflow → Decrease to Minimum
Airflow → Minimum Airflow → Return to Design
Airflow → Design Airflow)
▪ Particle Concentration at Rest: Must be verified
at the worst case scenario, i.e. @ Min. Flow
▪ Air Change Rate: It is optionally measured and can
be done at both airflow range limits.
Results compared to conventional system
The system has been thoroughly tested to check the
influence of the airflow reduction on the cleanroom
parameters (T, HR, particles, differential pressure,
recovery times…)
Temperature and relative humidity behaviour
The tests conducted reveal that the system reacts to
temperature and relative humidity excursions very fast,
even at lowest airflows. The temperature and the relative
humidity of the cleanroom remain stable during airflow
reduction and in operation at Minimum Flow.
Number of particles behaviour and recovery times
Operators and manual activities are the main source of
contamination. The dilution efficiency and air change
rates are directly related to recovery time of the classified
room: the higher the air change rate, the quicker the
recovery. Therefore, the Minimum Flow is restricted by
the user requirements during start-up: very low airflows
could lead to too high recovery times.
The results of the tests performed revealed that while the
installation is working in absence of personnel the
concentration of particles measured is insignificant. The
maximum admissible values for 0,5 µm and 5 µm are not
a limiting factor for airflow reduction in this case, as it is
a low-particle-generation closed process.
The AHU where SmartCR is implemented serves the
entire B-grade area, consisting of 9 cleanrooms of very
different sizes and geometries. The following table shows
the recovery times at both Design and Minimum Flow:
Figure 7. Ishikawa diagram showing how Critical Process Parameters / Critical Material Attributes impact on Critical Quality Attributes.
Table 1: Cleanroom CQA, CPP & CMA
Table 2: Cleanroom recovery times
CASE STUDY
.© Azbil Telstar. March 2020
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Differential pressures behaviour
Aseptic cleanrooms work at overpressure to avoid the
entry of contamination from C-grade surrounding
areas. This overpressure generates leaks of air
through doors and across pass-through openings for
conveyors. These leaks must be compensated with
additional supply airflow to keep overpressure within
the established limits.
The results of the tests conducted in the installation
show that this compensation of airflow is significant in
small rooms. While very low values of supply air are
enough for air dilution, particle removal and
temperature and relative humidity control, the limiting
factor for airflow reduction is the differential pressure
control.
Airflow reduction
The results of the conducted tests show that the air
change rate can be significantly reduced achieving
very low airflows with a remarkable energy saving,
always preserving the cleanroom within the specified
limits at all times.
In this particular case, the Minimum Flow has been
established as 56% of the Design Flow. With this
value, the nine cleanrooms remain inside the specified
limits at all times.
What would have happened if that small cleanroom
were not served by this AHU? Ignoring the differential
pressure control in this room, the system was forced
to continue reducing airflow while observing the
behavior of the other eight cleanrooms: a minimum
airflow of 35% of the Design Flow was reached.
Electrical consumption reduction
The electrical consumption of the fans has been measured
during the testing phase. Several scenarios have been
considered:
- At Design Flow: in order to know the electrical
consumption in conventional mode.
- In ECO mode
o At Minimum Flow: in order to measure the
minimum electrical consumption that could be
expected.
o In operating conditions, the SmartCR varies the
supply airflow to keep the cleanroom within
specifications, increasing the airflow to
compensate perturbations. During commissioning,
perturbations were produced to study the behavior
of the system: it was observed that the HVAC run
at Minimum Flow even when operators entered the
cleanroom to execute regular operations. In order
to challenge the system, further tests were
conducted during the start-up and SAT of the
aseptic filling line, with up to 5 technicians
performing tests on machines and changing
formats.
Figure 8: Comparison of Design Flow and Minimum flow values obtained in this particular case
Figure 9: Average electrical consumption of AHU working in conventional mode (Fixed Supply airflows)
CASE STUDY
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The fan electrical reduction observed is 76%-77%
with an associated expected saving in HEPA filter
replacement due to clogging of at least 29%.
Finally, even if the installation was designed to work in
recirculation mode, the system was put in operation
without air recirculation (100% of fresh air in the system)
to measure the potential consumption savings.
As expected, the electrical consumption of the single-pass
configuration is higher than the one measured in
recirculation mode at both Design and Minimum Flow but
still reaching an electrical consumption reduction of 76-
77%
Conclusions
The SmartCR is a robust HVAC system specially conceived
for high quality demanding pharmaceutical industry
seeking to reduce energy costs and environment impact.
Depending on the installation (geometry, configuration),
the process (closed / particle generating) and the HVAC
requirements (recirculation allowed / 100% fresh air-
100% exhaust air), can reach very high percentages of
airflow reduction with a consequent energy saving. It
ensures cleanrooms are within specifications at all times
and reacts to perturbations, keeping the stability of the
system.
The installation is fully qualified and the system is
validated. This meets the latest trends in the industry in
regards to quality regulations. A risk-based methodology
has been applied during its entire development,
implementation, commissioning and qualification.
Telstar CRS Pharmaceutical Technology Manager
Ana Fernández García, Pharmaceutical Technology Manager at Telstar’s CRS Engineering,
holds a MEng in Industrial Engineering from the UPM (Madrid, Spain) together with a MEng
in Chemical Engineering from CPE (Lyon, France). After some years working in the
Pharmaceutical industry, Ana jointed the Engineering Department at Telstar in 2007,
participating in and managing a wide variety of cleanroom engineering, construction and
turnkey projects. Since 2017, she’s in charge of the Conceptual Designs.
Figure 10: Average electrical consumption of AHU working in ECO mode.
Perturbations due to filling line start-up and SAT performed in September and October.
RECIRCULATION MODE
Averages values of electrical consumption
1,96 kWh
3-5,5 kWh
8,5 kWh
SINGLE-PASS MODE
Averages values of electrical consumption
2,8 kWh
12,7 kWh
Figure 11: Energy savings with SmartCR
CASE STUDY
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About Telstar Telstar, part of the azbil Group, is a company specialized in the development of engineering &
construction projects, integrated process equipment and GMP consultancy solutions, including turnkey
projects and critical installations, for companies associated with Life & Health Sciences (pharmaceutical
& biotechnology, healthcare, cosmetic, veterinary and food & beverage industries, hospitals, laboratories
& research centers). Acknowledged as one of the 10 major suppliers for the pharmaceutical industry,
Telstar is one of the few international manufacturers able to offer integrated process solutions for the
biopharmaceutical industry with in-house sterilization, freeze drying, containment, process water &
waste treatment, clean air and cold storage technologies.
www.telstar.com